1. Technical Field
The present invention generally relates to a pharmaceutical excipient. More particularly, the present invention relates to a pharmaceutical microemulsion excipient and method of making pharmaceutical compositions.
2. Background Art
It is well known in the art that there are solid drugs which are scarcely soluble in water. Due to their low solubilities, these drugs have a correspondingly low degree of bioavailability.
Several prior art processes have been developed in efforts to increase the solubility and, hence, the bioavailability of poorly soluble pharmaceuticals or drugs. One such prior art process discloses the use of water-soluble high-molecular weight substances having low melting points, such as Carbowax, in combination with an insoluble drug. However, compositions prepared by this process possess poor redispersibility in water due to the low melting point and, therefore, are undesirable as pharmaceutical excipients.
Other methods of increasing the aqueous dissolution rate of poorly water-soluble drugs include the use of organic solvents to solubilize the poorly water-soluble drug or pharmaceutical composition. One such method is disclosed in U.S. Pat. No. 4,540,602 to Motoyama et al., issued Sep. 10, 1985, which discloses a process for the preparation of activated pharmaceutical compositions containing a solid drug that is scarcely soluble in water. The method includes the steps of dissolving or solubilizing a solid drug, that is highly insoluble in water, in a low-boiling point hydrophobic organic solvent such as lecithin. The solubilized drug is then emulsified in the presence of a water-soluble, high-molecular weight substance, such as gelatin, and the drug is removed from the emulsion.
The method disclosed in the Motoyama et al. reference solubilizes the drug and then resolidifies/recrystalizes the drug in a water-soluble matrix such as gelatin or lecithin. The Motoyama et al. method requires the use of organic solvents in order to solubilize the drug. This method has several inherent disadvantages or drawbacks. First, since the drug is solubilized and then recrystalized, the recrystalized product must be reidentified since polymorphic changes can occur when the drug is recrystalized in a different solvent than the solvent originally used. Additionally, since the compounds of interest in the Motoyama patent are water-insoluble, organic solvents must be used in order to solubilize the drugs of interest. The use of organic solvents creates further problems with the health and safety aspects of organic solvents and the environmental unfriendliness and safety of organic solvents. All of these factors associated with the use of organic solvents considerably add to the cost of utilizing organic solvents in a method to increase the solubility of water-insoluble drugs as organic solvent recovery and containment devices are very costly. Other known surface active excipients can be affected by gastric pH or can be destructive to the intestinal mucosa.
In recent years, microemulsions have been extensively studied as a potential modality for oral drug delivery. Microemulsions are particularly useful for improving the oral absorption of water insoluble drugs, such as proteins, by utilizing self-microemulsifying drug delivery systems (SMEDDS) to enhance the solubility of the drug in the upper intestine [Ritschel, 1980]. In particular, microemulsions have gained considerable notoriety as drug delivery systems for peptides drugs.
Microemulsion systems contain a surfactant/co-surfactant blend which when added to a two-phase hydrophilic/lipophilic mixture, form a stable, optically clear, isotropic, colloidal system [Sarciaoux et al., 1995].
The interest in the use of microemulsions as oral drug delivery systems stems from their ability to spontaneously form (emulsify) at a given temperature, their considerable solublizing properties, the ability to be sterilized by filtration, and high physical stability [Sarciaoux et al., 1995]. Another desirable feature of these mixtures is their ability to form a microemulsion when exposed to gastrointestinal fluids. This type of behavior makes SMEDDS good candidates for vehicles for the oral delivery of lipophilic or slightly water-soluble drugs.
Farah et al., [1993] utilized SMEDDS technology in order to evaluate its potential for improving the in-vitro dissolution of the model drug indomethacin. Farah et al., [1993] utilized GELUCIRE with as the lipophilic phase, LABRAFAC (saturated C.sub.8 -C.sub.10 polyglycolated glyercides, HLB=10) as the surfactant, LAUROGLYCOL (propylene glycol laurate, HLB=4), and TRANSCUTOL (diethylene glycol monoethyl ether) as the co-surfactants, and indomethacin as the slightly water-soluble drug. Farah et al. [1993] found that the higher the HLB value of the surfactant and co-surfactant mixture, the higher the dissolution rate of the water insoluble drug. Farah et al. [1993] also showed that the in vitro dissolution kinetics of indomethacin from the SMEDDS in gastric medium was substantially improved as compared to indomethacin in the marketed powder form. Farah et al. [1993] further state that the performance of SMEDDS can be used to increase to bioavailability, however; Farah et al. [1993] did not teach any mechanism nor provide any data supporting the assertion that increased dissolution rate absolutely corresponds to an increase in the bioavailability of the drug. Additionally, Farah et al. [1993] do not teach nor suggest that the HLB value of the co-surfactant alone plays an important role in enhancing the bioavailability of water insoluble drugs, lipophilic drugs, or peptides. Farah et al. [1993] merely extrapolate that the bioavailability would be increased from the increased in vitro dissolution of indomethacin.
Therefore, it would be advantageous and desirable to have a method of increasing the dissolution and bioavailability of peptides, lipophilic and poorly water-soluble drugs which avoids the drawbacks of the prior art methods. Furthermore, it would be desirable to have a method which is completely aqueous-based in order to avoid the necessity for recharacterization of the pharmaceuticals or drugs according to the solubilization method disclosed above and also eliminating the cost and both health and environmental safety aspects of using organic solvents. It would also be advantageous and desirable to improve drug delivery via gastro-intestinal administration. It would be a further advantage to have a self-microemulsifying excipient formulation in which the bioavailability of poorly water-soluble drugs can be increased by utilizing a co-surfactant having a high HLB which can be applied to a drug in aqueous solution using standard manufacturing and equipment and which is safe and not destructive to the intestinal mucosa.
By combining the method and self-microemulsifying formulation of the present invention with poorly water-soluble drugs or pharmaceutical compositions, optimal advantage can be taken of the potential potency and efficacy of poorly water-soluble drugs by increasing their bioavailability. The present invention provides an improved method and formulation for providing poorly water-soluble drugs with a means for a greater bioavailability which includes all of the aforementioned mentioned advantages.